Asymmetric Aldol Reaction Catalyzed by the Self ... - CSJ Journals

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Oct 20, 2012 - control the access of the reactants and thus lead to a higher enantioselectivity in the chirality matched structures. The potential of using water as ...
doi:10.1246/cl.2012.1349 Published on the web October 20, 2012

1349

Asymmetric Aldol Reaction Catalyzed by the Self-assembled Nanostructures of L-Proline Containing Amphiphilic Dipeptide: A Morphological Dependence Mingzhe Shao, Qingxian Jin, Li Zhang,* and Minghua Liu* Beijing National Laboratory for Molecular Science, CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China (Received May 14, 2012; CL-120619; E-mail: [email protected], [email protected]) An L-proline containing amphiphilic dipeptide was found to self-assemble into nanosphere and nanofiber structures. These nanostructures could catalyze an asymmetric aldol reaction in water. Good reactivity and enantiomeric selectivity was observed for the nanosphere structure. Although the reaction could be catalyzed by the nanofiber structure, its enantioselectivity was remarkably decreased. It was suggested that the appropriate packing of the chiral assemblies can selectively control the access of the reactants and thus lead to a higher enantioselectivity in the chirality matched structures. The potential of using water as a reaction medium for asymmetric catalytic reaction has been increasingly realized,1­3 because water is a green solvent, providing an environmentally benign, safe, and low-cost reaction medium. In this context, micelles, vesicles, or emulsions have emerged as a powerful approach to achieve efficient asymmetric reaction in water, due to the generally increased local concentration of reactants and further providing favorable microenvironment for the catalytic reaction.3 In recent years, asymmetric aldol reactions catalyzed by proline derivatives have been reported to be useful C­C bondforming reactions and aldol products with excellent enantioselectivity are obtained.4 Generally, the aldol reactions are performed in organic solvents such as DMSO, DMF, and toluene, while the water as solvent often causes both low yield and enantioselectivity. However, considering that water is a desirable green solvent, more and more efforts have been devoted to the development of the asymmetric aldol reaction in water. Previous studies have shown that proline derivatives with hydrophobic chains could directly catalyze asymmetric aldol reaction of cyclohexanone and p-nitrobenzaldehyde in water.5 Proline-based compounds were also shown to be catalysts in water with the aid of polymer or surfactant.6,7 In addition, polystyrene (PS)-supported proline was reported to show stereochemical control of direct aldol reaction in water8 and so on.9 In this paper, we designed amphiphilic proline­tryptophan dipeptides and studied their effectiveness as a catalyst for aldol reaction in water. We have found that the dipeptide derivatives can self-assemble in water or form supramolecular gels in a mixture of DMSO and water, producing nanosphere and nanofiber structures, respectively. Interestingly, when these two nanostructures were used as catalyst, different enantioselectivity were observed. The molecular structures of the proline­tryptophan amphiphiles are shown in Figure 1. The self-assembly of PTC12 in water in the presence of trifluoroacetic acid (TFA) was characterized by scanning electron microscopy (SEM) and

Chem. Lett. 2012, 41, 1349­1350

Figure 1. Asymmetric aldol reaction of cyclohexanone with pnitrobenzaldehyde in water and the structures of catalysts.

Figure 2. (A) Particle size distribution of (a) PTC12 assemblies in water; (b) after addition of cyclohexanone and p-nitrobenzaldehyde; (c) after 8 h reaction. (B), (C) SEM image of PTC12 assemblies in water. (D) SEM image of PTC12 xerogel obtained in DMSO/water (1:2). Inset is the photo of the PTC12 supramolecular gel.

dynamic light scattering (DLS). The DLS measurements exhibited some particles with diameter about 115 « 45 nm (Figure 2A), which were subsequently observed by SEM. In SEM observation, the assemblies showed spherical nanoparticles with diameters of 90­150 nm (Figures 2B and 2C), indicating that the proline­tryptophan amphiphiles spontaneously assembled into nanosphere structures. On the other hand, when the dipeptide formed supramolecular gels in a mixture of DMSO and water (1:2 v/v), nanofiber structures were obtained, as shown in Figure 2D. The SEM revealed that the widths of the entangled fibers were 100­150 nm in diameter and the length extended to micrometer, typical of the nanofiber structures for physical gels.10,11

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1350 Table 1. Screening of catalysts in the direct asymmetric aldol reaction of cyclohexanone with p-nitrobenzaldehyde in water Entry 1 2 3 4 5 6 7 a

Catalyst

Additive

Solvent

Proline PT PTC10 PT2 C10 PTC12 PTC14 PTC12 gel

TFA TFA TFA TFA TFA TFA TFA

H2O H2O H2O H2O H2O H2O H2O

Yield/%a

ee/%b

0 0 83 50 87 79 80

® ® 83 27 90 80 20

b

Isolated yield. By Chiral-HPLC (Daicel Chiracel-AD column, cyclohexane/i-PrOH = 0.48:0.02, 0.5 mL min¹1); TFA is 20% (mol %) of aldehyde.

The aldol reaction of cyclohexanone and p-nitrobenzaldehyde was carried out in a water dispersion of amphiphilic dipeptide. In a typical experiment, 2 equiv of cyclohexanone to the aldehyde were used, and the concentration of catalyst was kept at 10% (mol %) of aldehyde. As for the reaction catalyzed by supramolecular gels, the supramolecular PTC12 gels were dispersed in the aqueous reaction system. After 8 h at room temperature in water, the reaction was complete. We then analyzed the yield and the enantiomeric excess of the product. The results are shown in Table 1. It is reported that aldol reactions are typically performed in organic solvents, such as DMSO, DMF, or chloroform. It is difficult to obtain desirable yield and ee value in water without modifying the proline, as observed in Entry 1. The dipeptide of proline and tryptophan also cannot catalyze the reaction in water, indicating that the tryptophan moiety does not contribute to enantiomeric selectivity. When the amphiphilic dipeptides were used as catalysts, great enhancement of yield and enantiomeric selectivity was achieved, as shown in Entries 3­6. It was noted that the hydrophobic chains affected the ee value of the product. With the hydrophobicity increased, especially when two hydrophobic chains were adopted, the yield and ee value of product decreased remarkably. The particle size distribution was monitored by DLS measurement during reaction. It was obvious that the particle size increased upon addition of the reactant to the aqueous system, which changed from 115 to 150 nm, indicating that the reactant existed in the aggregates instead of the bulk water. The particle was stable enough that the reaction did not destroy the structure of the assemblies, which was characterized by the DLS measurements after the reaction finished. The particle diameter remained at 150 nm, only with a little increase in multidispersity. As we mentioned above, the reactant of cyclohexanone and p-nitrobenzaldehyde existed in the assembly of PTC12, not only increasing its solubility in water, but being isolated to interact with bulk water directly. This attributed to the enhancement of enantiomeric selectivity. As for the reaction catalyzed by PTC12 supramolecular gels, moderate yield was obtained, suggesting that the reactivity was kept via the ordered assemblies. However, the ee value is much lower than that catalyzed by nanosphere structures, as shown in Entry 7. We suppose that the hydrogen bonding between amide moieties, which drive PTC12 to form supramolecular gels, made the proline moieties so close that the enantioselectivity was decreased. Figure 3 illustrates the packing difference of the functional groups of the nanospheres and nanofibers. In the nanosphere structure, the neighboring functional groups have Chem. Lett. 2012, 41, 1349­1350

Figure 3. (A) The nanosphere structures formed by PTC12 in water. (B) The scheme of PTC12 supramolecular gels.

some spaces for the reactants to access. While in the nanofiber structures, the neighboring aromatic rings packed so closely that the reactants are difficult to access. In addition, the curvature of nanosphere structures probably contributes to the high enantiomeric selectivity.12­14 In summary, the amphiphilic proline based dipeptide has been synthesized and its self-assembled nanospheres have been proven to be an efficient catalyst for the direct asymmetric aldol reactions in water. The hydrophobicity of proline derivatives has a profound effect on the reaction stereoselectivity. In addition, the proline dipeptide can form supramolecular gels in the mixed solvent of DMSO and water. The enantiomeric selectivity was found to be related to the assembly of catalyst molecules. The enantiomeric selectivity of aldol reaction catalyzed by PTC12 gels with nanofiber structures was found to be lower than that catalyzed by nanosphere structures. It is expected that the supramolecular catalyst obtained through the self-assembly can contribute to green chemistry. This work was supported by the Basic Research Development Program (Nos. 2010CB833305 and 2009CB930802), the National Natural Science Foundation of China (Nos. 91027042 and 21021003), and the Fund of the Chinese Academy of Sciences. Paper based on a presentation made at the International Association of Colloid and Interface Scientists, Conference (IACIS2012), Sendai, Japan, May 13­18, 2012. References 1 S. Kobayashi, K. Manabe, Acc. Chem. Res. 2002, 35, 209. 2 C.-J. Li, Chem. Rev. 2005, 105, 3095. 3 S. Luo, H. Xu, J. Li, L. Zhang, X. Mi, X. Zheng, J.-P. Cheng, Tetrahedron 2007, 63, 11307. 4 W. Notz, F. Tanaka, C. F. Barbas, III, Acc. Chem. Res. 2004, 37, 580. 5 N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka, C. F. Barbas, III, J. Am. Chem. Soc. 2006, 128, 734. 6 M. Lei, L. Shi, G. Li, S. Chen, W. Fang, Z. Ge, T. Cheng, R. Li, Tetrahedron 2007, 63, 7892. 7 Y. Hayashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya, M. Shoji, Angew. Chem., Int. Ed. 2006, 45, 5527. 8 D. Font, C. Jimeno, M. A. Pericàs, Org. Lett. 2006, 8, 4653. 9 Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima, M. Shoji, Angew. Chem., Int. Ed. 2006, 45, 958. 10 R. Oda, in Molecular Gels, ed by R. G. Weiss, P. Terech, Springer, The Netherlands, 2006, Chap. 16. doi:10.1007/1-4020-3689-2_17. 11 M. George, R. G. Weiss, Acc. Chem. Res. 2006, 39, 489. 12 K. Balamurugan, E. R. A. Singam, V. Subramanian, J. Phys. Chem. C 2011, 115, 8886. 13 D. Wang, R. J. Nap, I. Lagzi, B. Kowalczyk, S. Han, B. A. Grzybowski, I. Szleifer, J. Am. Chem. Soc. 2011, 133, 2192. 14 Q. Jin, L. Zhang, H. Cao, T. Wang, X. Zhu, J. Jiang, M. Liu, Langmuir 2011, 27, 13847.

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